Immuno-modulation in Amyotrophic Lateral Sclerosis- a Phase II Study of Safety and Activity of Low Dose Interleukin-2 (IMODALS)

• ClinicalTrials.gov Identifier: NCT02059759
• Recruitment Status: Completed
• First Posted: February 11, 2014
• Last Update Posted: June 1, 2016
• Sponsor: Centre Hospitalier Universitaire de Nīmes
• Information provided by (Responsible Party): Centre Hospitalier Universitaire de Nīmes

Study Description

Brief Summary:

The primary objective is to evaluate in ALS patients the regulatory T cell early response to two low-doses of IL-2 at 1 and 2 MIU per day after one course of 5 consecutive days comparatively to placebo.

Condition or disease	Intervention/treatment	Phase
Amyotrophic Lateral Sclerosis	Drug: Placebo; Drug: 1.0 MIU IL-2 per day; Drug: 2.0 MIU IL-2 per day	Phase 2

Detailed Description:

This is a phase II study on ld-IL-2 as a therapeutic agent for ALS which aims at defining the activity and safety of a range a doses for subsequent use of the best dose in a phase II/III trial. For ethical reasons, ld-IL-2 must be tested as an add-on therapy to riluzole hence all patients will need to be treated with riluzole for at least three months prior to entry. A randomized (1:1:1), placebo-controlled, double-blind, parallel group trial will be carried out to assess ld-IL-2 activity on regulatory T cells and immuno-inflammatory markers in ALS patients treated for 3 months (5 days every four weeks repeated three times).

The secondary objectives of this study are:

A. To evaluate maintenance of Tcell response after three repeated 5-day courses at one course every four weeks for 12 weeks.

B. To evaluate the safety of ld-IL-2 therapy in an ALS population, with an overall follow-up of 6 months (up to 15 weeks after last administration); C. To evaluate functional changes throughout the study; D. To evaluate changes in other pre-defined blood cytology parameters, and a blood biomarker for axonal damage.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 36 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Immuno-modulation in Amyotrophic Lateral Sclerosis- a Phase II Study of Safety and Activity of Low Dose Interleukin-2
• Study Start Date: September 2015
• Actual Primary Completion Date: December 2015
• Actual Study Completion Date: May 2016

Arms and Interventions

Arm	Intervention/treatment
Placebo Comparator: Placebo; Patients in this arm will receive sub-cutaneous injections of placebo (same vehicle as for experimental arms, and same volume) for 5 consecutive days at the beginning of three consecutive months (a total of 15 injections, 5 per month for 3 months). Intervention: Placebo	Drug: Placebo; Patients in this arm will receive sub-cutaneous injections of placebo (same vehicle as for experimental arms, and same volume) for 5 consecutive days at the beginning of three consecutive months (a total of 15 injections, 5 per month for 3 months).
Experimental: 1.0 IL-2; Patients in this arm will receive sub-cutaneous injections corresponding to 1.0 MIU of IL-2 per injection for 5 consecutive days at the beginning of three consecutive months (a total of 15 injections, 5 per month for 3 months). Intervention: 1.0 MIU IL-2 per day	Drug: 1.0 MIU IL-2 per day; Patients in this arm will receive sub-cutaneous injections corresponding to 1.0 MIU of IL-2 per injection for 5 consecutive days at the beginning of three consecutive months (a total of 15 injections, 5 per month for 3 months).; Other Names: Aldesleukine; Proleukin
Experimental: 2.0 IL-2; Patients in this arm will receive sub-cutaneous injections corresponding to 2.0 MIU of IL-2 per injection for 5 consecutive days at the beginning of three consecutive months (a total of 15 injections, 5 per month for 3 months). Intervention: 2.0 MIU IL-2 per day	Drug: 2.0 MIU IL-2 per day; Patients in this arm will receive sub-cutaneous injections corresponding to 2.0 MIU of IL-2 per injection for 5 consecutive days at the beginning of three consecutive months (a total of 15 injections, 5 per month for 3 months).; Other Names: Aldesleukine; Proleukin

Outcome Measures

Primary Outcome Measures :

1. CD4+ CD25+ CD127- FoxP3+(Treg) cells: change in percentage of total lymphocytes [ Time Frame: Day 8 ]
   Treg refers to regulatory T cells

Secondary Outcome Measures :

1. Presence/absence of specific, pre-defined adverse events. [ Time Frame: Day 1 ]
   The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.
2. Presence/absence of specific, pre-defined adverse events. [ Time Frame: Day 2 ]
   The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.
3. Presence/absence of specific, pre-defined adverse events. [ Time Frame: Day 3 ]
   The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.
4. Presence/absence of specific, pre-defined adverse events. [ Time Frame: Day 4 ]
   The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.
5. Presence/absence of specific, pre-defined adverse events. [ Time Frame: Day 5 ]
   The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.
6. Presence/absence of specific, pre-defined adverse events. [ Time Frame: Day 6 ]
   The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.
7. Presence/absence of specific, pre-defined adverse events. [ Time Frame: Day 7 ]
   The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.
8. Presence/absence of specific, pre-defined adverse events. [ Time Frame: Day 8 ]
   The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.
9. Presence/absence of specific, pre-defined adverse events. [ Time Frame: Day 29 ]
   The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.
10. Presence/absence of specific, pre-defined adverse events. [ Time Frame: Day 30 ]
    The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.
11. Presence/absence of specific, pre-defined adverse events. [ Time Frame: Day 31 ]
    The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.
12. Presence/absence of specific, pre-defined adverse events. [ Time Frame: Day 32 ]
    The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.
13. Presence/absence of specific, pre-defined adverse events. [ Time Frame: Day 33 ]
    The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.
14. Presence/absence of specific, pre-defined adverse events. [ Time Frame: Day 34 ]
    The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.
15. Presence/absence of specific, pre-defined adverse events. [ Time Frame: Day 35 ]
    The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.
16. Presence/absence of specific, pre-defined adverse events. [ Time Frame: Day 36 ]
    The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.
17. Presence/absence of specific, pre-defined adverse events. [ Time Frame: Day 57 ]
    The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.
18. Presence/absence of specific, pre-defined adverse events. [ Time Frame: Day 58 ]
    The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.
19. Presence/absence of specific, pre-defined adverse events. [ Time Frame: Day 59 ]
    The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.
20. Presence/absence of specific, pre-defined adverse events. [ Time Frame: Day 60 ]
    The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.
21. Presence/absence of specific, pre-defined adverse events. [ Time Frame: Day 61 ]
    The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.
22. Presence/absence of specific, pre-defined adverse events. [ Time Frame: Day 62 ]
    The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.
23. Presence/absence of specific, pre-defined adverse events. [ Time Frame: Day 63 ]
    The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.
24. Presence/absence of specific, pre-defined adverse events. [ Time Frame: Day 64 ]
    The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.
25. Presence/absence of abnormal vital signs [ Time Frame: Day 1 ]
    (based on a systematic check of vital signs: pulse, blood pressure, oxymetry, temperature)
26. Presence/absence of abnormal vital signs [ Time Frame: Day 8 ]
    (based on a systematic check of vital signs: pulse, blood pressure, oxymetry, temperature)
27. Presence/absence of abnormal vital signs [ Time Frame: Day 29 ]
    (based on a systematic check of vital signs: pulse, blood pressure, oxymetry, temperature)
28. Presence/absence of abnormal vital signs [ Time Frame: Day 57 ]
    (based on a systematic check of vital signs: pulse, blood pressure, oxymetry, temperature)
29. Presence/absence of abnormal vital signs [ Time Frame: Day 64 ]
    (based on a systematic check of vital signs: pulse, blood pressure, oxymetry, temperature)
30. Presence/absence of abnormal vital signs [ Time Frame: Week 13 ]
    (based on a systematic check of vital signs: pulse, blood pressure, oxymetry, temperature)
31. Presence/absence of abnormal vital signs [ Time Frame: Week 25 ]
    (based on a systematic check of vital signs: pulse, blood pressure, oxymetry, temperature)
32. MedDRA classification of all adverse events throughout the study [ Time Frame: Week 25 ]
    MedDRA refers to "Medical Dictionary for Regulatory Activities"
33. Thyroid function: blood T4 [ Time Frame: Baseline (day 0 to day -15) ]
34. Thyroid function: blood T4 [ Time Frame: Week 13 ]
35. Thyroid function: blood TSH [ Time Frame: Baseline (day 0 to day -15) ]
36. Thyroid function: blood TSH [ Time Frame: Week 13 ]
37. Presence/absence of clinically significant abnormality on a lung x-ray [ Time Frame: Baseline (day 0 to day -15) ]
38. Presence/absence of clinically significant abnormality on a lung x-ray [ Time Frame: Week 13 ]
39. Presence/absence of clinically significant abnormality on an electrocardiogram [ Time Frame: Baseline (day 0 to day -15) ]
40. Presence/absence of clinically significant abnormality on an electrocardiogram [ Time Frame: Week 13 ]
41. Presence/absence of a clinically significant abnormality among routine laboratory tests [ Time Frame: Day 1 ]

    The routine blood tests considered are:

    • haemogram (hemoglobin, hematocrit, red blood cell count, white blood cell count, leukocyte formula, platelets, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration )
    • blood biochemistry (ionogram, urea, creatinine, glucose, C reactive protein, procalcitonin, protein, albumin)
    • liver function panel (aspartate transaminase, alanine transaminase, gamma-glutamyl transpeptidase, bilirubin)
    • iron metabolism (iron, ferritin, transferrin)
42. Presence/absence of a clinically significant abnormality among routine laboratory tests [ Time Frame: Day 8 ]

    The routine blood tests considered are:

    • haemogram (hemoglobin, hematocrit, red blood cell count, white blood cell count, leukocyte formula, platelets, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration)
    • blood biochemistry (ionogram, urea, creatinine, glucose, C reactive protein, procalcitonin, protein, albumin)
    • liver function panel (aspartate transaminase, alanine transaminase, gamma-glutamyl transpeptidase, bilirubin)
    • iron metabolism (iron, ferritin, transferrin)
43. Presence/absence of a clinically significant abnormality among routine laboratory tests [ Time Frame: Day 29 ]

    The routine blood tests considered are:

    • haemogram (hemoglobin, hematocrit, red blood cell count, white blood cell count, leukocyte formula, platelets, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration)
    • blood biochemistry (ionogram, urea, creatinine, glucose, C reactive protein, procalcitonin, protein, albumin)
    • liver function panel (aspartate transaminase, alanine transaminase, gamma-glutamyl transpeptidase, bilirubin)
    • iron metabolism (iron, ferritin, transferrin)
44. Presence/absence of a clinically significant abnormality among routine laboratory tests [ Time Frame: Day 57 ]

    The routine blood tests considered are:

    • haemogram (hemoglobin, hematocrit, red blood cell count, white blood cell count, leukocyte formula, platelets, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration)
    • blood biochemistry (ionogram, urea, creatinine, glucose, C reactive protein, procalcitonin, protein, albumin)
    • liver function panel (aspartate transaminase, alanine transaminase, gamma-glutamyl transpeptidase, bilirubin)
    • iron metabolism (iron, ferritin, transferrin)
45. Presence/absence of a clinically significant abnormality among routine laboratory tests [ Time Frame: Day 64 ]

    The routine blood tests considered are:

    • haemogram (hemoglobin, hematocrit, red blood cell count, white blood cell count, leukocyte formula, platelets, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration)
    • blood biochemistry (ionogram, urea, creatinine, glucose, C reactive protein, procalcitonin, protein, albumin)
    • liver function panel (aspartate transaminase, alanine transaminase, gamma-glutamyl transpeptidase, bilirubin)
    • iron metabolism (iron, ferritin, transferrin)
46. Presence/absence of a clinically significant abnormality among routine laboratory tests [ Time Frame: Week 13 ]

    The routine blood tests considered are:

    • haemogram (hemoglobin, hematocrit, red blood cell count, white blood cell count, leukocyte formula, platelets, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration)
    • blood biochemistry (ionogram, urea, creatinine, glucose, C reactive protein, procalcitonin, protein, albumin)
    • liver function panel (aspartate transaminase, alanine transaminase, gamma-glutamyl transpeptidase, bilirubin)
    • iron metabolism (iron, ferritin, transferrin)
47. Presence/absence of a clinically significant abnormality among routine laboratory tests [ Time Frame: Week 25 ]

    The routine blood tests considered are:

    • haemogram (hemoglobin, hematocrit, red blood cell count, white blood cell count, leukocyte formula, platelets, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration)
    • blood biochemistry (ionogram, urea, creatinine, glucose, C reactive protein, procalcitonin, protein, albumin)
    • liver function panel (aspartate transaminase, alanine transaminase, gamma-glutamyl transpeptidase, bilirubin)
    • iron metabolism (iron, ferritin, transferrin)
48. Vital capacity (% of normal) [ Time Frame: Baseline (day 0 to day -15) ]
    This is a measure of respiratory function.
49. Vital capacity (% of normal) [ Time Frame: Day 1 ]
    This is a measure of respiratory function.
50. Vital capacity (% of normal) [ Time Frame: Week 13 ]
    This is a measure of respiratory function.
51. Vital capacity (% of normal) [ Time Frame: Week 25 ]
    This is a measure of respiratory function.
52. The ALSFRS Questionnaire [ Time Frame: Day 1 ]
53. The ALSFRS Questionnaire [ Time Frame: Day 29 ]
54. The ALSFRS Questionnaire [ Time Frame: Day 57 ]
55. The ALSFRS Questionnaire [ Time Frame: Week 13 ]
56. The ALSFRS Questionnaire [ Time Frame: Week 25 ]
57. Tregs (absolute number and % CF4+ cells) [ Time Frame: Day 1 ]
58. Tregs (absolute number and % CF4+ cells) [ Time Frame: Day 8 ]
59. Tregs (absolute number and % CF4+ cells) [ Time Frame: Day 57 ]
60. Tregs (absolute number and % CF4+ cells) [ Time Frame: Day 64 ]
61. Tregs (absolute number and % CF4+ cells) [ Time Frame: Week 13 ]
62. Tregs (absolute number and % CF4+ cells) [ Time Frame: Week 25 ]
63. Total lymphocyte number [ Time Frame: Day 1 ]
64. Total lymphocyte number [ Time Frame: Day 8 ]
65. Total lymphocyte number [ Time Frame: Day 57 ]
66. Total lymphocyte number [ Time Frame: Day 64 ]
67. Total lymphocyte number [ Time Frame: Week 13 ]
68. Total lymphocyte number [ Time Frame: Week 25 ]
69. CD56+(NK), CD19+(B), CD3+, CD4+, CD8+ cell populations: numbers and percentages of total lymphocytes [ Time Frame: Day 1 ]
70. CD56+(NK), CD19+(B), CD3+, CD4+, CD8+ cell populations: numbers and percentages of total lymphocytes [ Time Frame: Day 8 ]
71. CD56+(NK), CD19+(B), CD3+, CD4+, CD8+ cell populations: numbers and percentages of total lymphocytes [ Time Frame: Day 57 ]
72. CD56+(NK), CD19+(B), CD3+, CD4+, CD8+ cell populations: numbers and percentages of total lymphocytes [ Time Frame: Day 64 ]
73. CD56+(NK), CD19+(B), CD3+, CD4+, CD8+ cell populations: numbers and percentages of total lymphocytes [ Time Frame: Week 13 ]
74. CD56+(NK), CD19+(B), CD3+, CD4+, CD8+ cell populations: numbers and percentages of total lymphocytes [ Time Frame: week 25 ]
75. effector T cells: number and % of CD4 cells [ Time Frame: Day 1 ]
    This is measured as CD4+ lymphocytes minus regulatory T cells
76. effector T cells: number and % of CD4 cells [ Time Frame: Day 8 ]
    This is measured as CD4+ lymphocytes minus regulatory T cells
77. effector T cells: number and % of CD4 cells [ Time Frame: Day 57 ]
    This is measured as CD4+ lymphocytes minus regulatory T cells
78. effector T cells: number and % of CD4 cells [ Time Frame: Day 64 ]
    This is measured as CD4+ lymphocytes minus regulatory T cells
79. effector T cells: number and % of CD4 cells [ Time Frame: Week 13 ]
    This is measured as CD4+ lymphocytes minus regulatory T cells
80. effector T cells: number and % of CD4 cells [ Time Frame: Week 25 ]
    This is measured as CD4+ lymphocytes minus regulatory T cells
81. Phosphorylated neurofilament heavy protein (pNfH) levels in serum [ Time Frame: day 1 ]
82. Light chain neurofilament levels in serum [ Time Frame: Day 1 ]
83. Light chain neurofilament levels in serum [ Time Frame: Week 13 ]

Other Outcome Measures:

1. Age (years) [ Time Frame: Baseline ]
2. Sex (male/female) [ Time Frame: Baseline ]
3. Body mass index (kg/m^2) [ Time Frame: Baseline ]
4. Disease duration from date of first symptoms (fatigue, weakness) [ Time Frame: Baseline ]
5. The patient's current Riluzole posology [ Time Frame: Baseline to week 25 ]
6. The patient's currentposology for other concomitant treatments [ Time Frame: Baseline to week 25 ]
7. Description of concomitant treatments, if any [ Time Frame: Throughout study, up to 25 weeks ]
8. Routine serology results dating to within the last 30 days: HIV-1 (positive/negative ?) [ Time Frame: Baseline ]
9. Routine serology results dating to within the last 30 days: Epstein Barr Virus (positive/negative ?) [ Time Frame: Baseline ]
10. Routine serology results dating to within the last 30 days: cytomegalovirus (positive/negative ?) [ Time Frame: Baseline ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• The patient has been correctly informed
• The patient must have given his/her informed and signed consent.
• The patient must be insured or beneficiary of a health insurance plan.
• The patient is at least 18 years old and less than 75 years old
• Probable, or laboratory-supported probable or definite ALS as defined by El Escorial Revised ALS diagnostic criteria (according to Airlie House Conference 1988)
• Stable on riluzole treatment for more than 3 months with liver function test results < 2ULN
• Disease duration ≤ 5 years
• Vital capacity ≥ 70% of normal
• Ability to swallow without the requirement for nasogastric or PEG feeding
• Agreement for patient to use an adequate method of contraception throughout the study and for 2 weeks after post study visit
• The patient is available and willing to participate in seven study visits occurring at the CHU within the next six months

Exclusion Criteria:

• The patient is participating in another interventional study
• Within the past three months, the patient has participated in another interventional
• The patient is in an exclusion period determined by a previous study
• The patient is under judicial protection
• The patient is an adult under guardianship
• The patient refuses to sign the consent
• It is impossible to correctly inform the patient
• Other life threatening disease
• Presence of contra-indicated concomitant treatments or with potential neuroprotective benefit (see section 11.2 of the protocol)
• Presence of tracheostomy or non-invasive ventilation
• Use of Percutaneous endoscopic gastrostomy (PEG) or nasogastric tube
• Presence of clinical infection (treated or untreated)
• Positive serology for CMV, EBV (confirmed by viral load), or HIV
• Vaccination within 8 weeks prior to first experimental dosing
• Other disease precluding functional assessments
• Cancer within the past 5 years (except stable non-metastatic basal cell skin carcinoma or in situ carcinoma of the cervix)
• Severe cardiac or pulmonary disease
• Documented auto-immune disorders except asymptomatic Hashimoto thyroiditis
• Women of child bearing age without contraception or pregnant or breast feeding
• Any clinically significant laboratory abnormality (excepting cholesterol, triglyceride and glucose)

Contacts and Locations

Locations

France

CHRU de Montpellier - Hôpital Gui de Chauliac

Montpellier, France, 34295

Sponsors and Collaborators

Centre Hospitalier Universitaire de Nīmes

Investigators

• Study Director: Raul Juntas-Morales, MD; CHRU de Montpellier

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Camu W, Mickunas M, Veyrune JL, Payan C, Garlanda C, Locati M, Juntas-Morales R, Pageot N, Malaspina A, Andreasson U, Kirby J, Suehs C, Saker S, Masseguin C, De Vos J, Zetterberg H, Shaw PJ, Al-Chalabi A, Leigh PN, Tree T, Bensimon G. Repeated 5-day cycles of low dose aldesleukin in amyotrophic lateral sclerosis (IMODALS): A phase 2a randomised, double-blind, placebo-controlled trial. EBioMedicine. 2020 Sep;59:102844. doi: 10.1016/j.ebiom.2020.102844. Epub 2020 Jul 7.

• Responsible Party: Centre Hospitalier Universitaire de Nīmes
• ClinicalTrials.gov Identifier: NCT02059759
• Other Study ID Numbers: LOCAL/2014/WC-01; 2014-001327-71 ( EudraCT Number )
• First Posted: February 11, 2014
• Last Update Posted: June 1, 2016
• Last Verified: May 2016

Keywords provided by Centre Hospitalier Universitaire de Nīmes:

low-dose interleukin 2

Additional relevant MeSH terms:

Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Sclerosis; Interleukin-2; Pathologic Processes; Neurodegenerative Diseases; Nervous System Diseases; Neuromuscular Diseases; Spinal Cord Diseases; Central Nervous System Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Metabolic Diseases; Aldesleukin; Antineoplastic Agents; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anti-HIV Agents; Anti-Retroviral Agents; Antiviral Agents; Anti-Infective Agents